Not applicable.
The invention relates generally to the fields of medicine and delivery of therapeutically active substances. More particularly, the invention relates to implantable brachytherapy devices.
Radioactive seed therapy, commonly referred to as brachytherapy, is an established technique for treating various medical conditions, most notably prostate cancer. In a typical application of brachytherapy for treating prostate cancer, about 50-150 small seeds containing a radioisotope that emits a relatively short-acting type of radiation are surgically implanted in the diseased tissue. Because the seeds are localized near the diseased tissue, the radiation they emit is thereby concentrated on the cancerous cells and not on distantly located healthy tissue. In this respect, brachytherapy is advantageous over conventional external beam radiation.
A number of devices have been employed to implant radioactive seeds into tissues. See, e.g., U.S. Pat. Nos. 2,269,963 to Wappler; U.S. Pat. No. 4,402,308 to Scott; U.S. Pat. No. 5,860,909 to Mick; and U.S. Pat. No. 6,007,474 to Rydell. In a typical protocol for treating prostate cancer, an implantation device having a specialized needle is inserted through the skin between the rectum and scrotum into the prostate to deliver radioactive seeds to the prostate. The needle can be repositioned or a new needle used for other sites in the prostate where seeds are to be implanted. Typically, 20-40 needles are used to deliver between about 50-150 seeds per prostate. A rectal ultrasound probe is used to track the position of the needles. Once the end of a given needle is positioned in a desired location, a seed is forced down the bore of the needle so that it becomes lodged at that location.
As the seeds are implanted in the prostate as desired, the needles are removed from the patient. Over the ensuing several months the radiation emitted from the seeds kills the cancerous cells. Surgical removal of the seeds is usually not necessary because the type of radioisotope generally used decays over the several month period so that very little radiation is emitted from the seeds after this time.
Currently marketed radioactive seeds take the form of a capsule encapsulating a radioisotope. See, e.g., Symmetra(copyright) I-125 (Bebig GmbH, Germany); IoGold(trademark) I-125 and IoGold(trademark) Pd-103 (North American Scientific, Inc., Chatsworth, Calif.); Best(copyright) I-125 and Best Pd-103 (Best Industries, Springfield, Va.); Brachyseed(copyright) I-125 (Draximage, Inc., Canada); Intersource(copyright) Pd-103 (International Brachytherapy, Belgium); Oncoseed(copyright) I-125 (Nycomed Amersham, UK); STM 1250 I-125 (Sourcetech Medical, Carol Stream, Ill.); Pharmaseed(copyright) I-125 (Syncor, Woodland Hills, Calif.); Prostaseed(trademark) I-125 (Urocor, Oklahoma City, Okla.); and I-plant(copyright) I-125 (Implant Sciences Wakefield, Mass.). The capsule of these seeds is made of a biocompatible substance such as titanium or stainless steel, and is tightly sealed to prevent leaching of the radioisotope. The capsule is sized to fit down the bore of one of the needles used in the implantation device. Since most such needles are about 18 gauge, the capsule typically has a diameter of about 0.8 mm and a length of about 4.5-mm.
The two radioisotopes most commonly used in prostate brachytherapy seeds are iodine (I-125) and palladium (Pd-103). Both emit low energy irradiation and have half-life characteristics ideal for treating tumors. For example, I-125 seeds decay at a rate of 50% every 60 days, so that using typical starting doses their radioactivity is almost exhausted after ten months. Pd-103 seeds decay even more quickly, losing half their energy every 17 days so that they are nearly inert after only 3 months.
Radioactive brachytherapy seeds may also contain other components. For example, to assist in tracking their proper placement using standard X-ray imaging techniques, such seeds may contain a radiopaque marker. Markers are typically made of high atomic number (i.e., xe2x80x9chigh Zxe2x80x9d) elements or alloys or mixtures containing such elements. Examples of these include platinum, iridium, rhenium, gold, tantalum, lead, bismuth alloys, indium alloys, solder or other alloys with low melting points, tungsten, and silver. Many radiopaque markers are currently being marketed including: platinum/iridium markers (Draximage, Inc. and International Brachytherapy), gold rods (Bebig GmbH), gold/copper alloy markers (North American Scientific), palladium rods (Syncor), tungsten markers (Best Industries), silver rods (Nycomed Amersham), silver spheres (International Isotopes Inc. and Urocor), and silver wire (Implant Sciences Corp.). Other radiopaque markers include polymers impregnated with various substances (see, e.g., U.S. Pat. No. 6,077,880).
A number of different U.S. patents disclose technology relating to brachytherapy. For example, U.S. Pat. No. 3,351,049 to Lawrence discloses the use of a low-energy X-ray-emitting interstitial implant as a brachytherapy source. In addition, U.S. Pat. No. 4,323,055 to Kubiatowicz; U.S. Pat. No. 4,702,228 to Russell; U.S. Pat. No. 4,891,165 to Suthanthiran; U.S. Pat. No. 5,405,309 to Carden; U.S. Pat. No. 5,713,828 to Coniglione; U.S. Pat. No. 5,997,463 to Cutrer; U.S. Pat. No. 6,066,083 to Slater; and 6,074,337 to Tucker disclose technologies relating to brachytherapy devices.
The invention relates to a brachytherapy seed that includes a drug or other therapeutically active substance that can be delivered to a subject upon implantation into the subject through the bore of a brachytherapy implantation needle. Because the brachytherapy seeds of the invention can be sized and shaped to fit through the bore of a brachytherapy implantation needle, they are suitable for use with brachytherapy seed implantation instruments such as an implant needle, a Henschke, Scott, or Mick applicator, or a like device such as a Royal Marsden gold grain gun. A drug or other therapeutically active substance can be included in the seed in addition to, or as an alternative to, a radioisotope. A drug or other therapeutically active substance can also be associated with a biodegradable component so that its rate of release in the implantation site can be controlled according to the rate that the biodegradable substance decomposes at the implantation site. Thus, like conventional radioactive brachytherapy seeds, the seeds within the invention can be precisely implanted in many different target tissues without the need for invasive surgery. And similar to the radiation emitted from conventional brachytherapy seeds, the therapeutically active substance included within a seed of the invention can be delivered in a controlled fashion over a relatively long period of time (e.g., weeks, months, or longer periods). Moreover, because concentrations of the therapeutically active substance will be greater at the implantation site (e.g., the diseased tissue), any potential deleterious effect of the therapeutically active substance on healthy tissue located away from the implantation site will be reduced.
Depending on the particular application, the brachytherapy seeds of the present invention offer other advantages. Among these, for example, compared to conventional systemic administration (e.g., oral or intravenous delivery) of therapeutically active substances, the brachytherapy seeds of the invention can provide higher and more consistent concentrations of a therapeutically active substance to a target tissue. They can also eliminate the need for repeated injections as well as circumvent delivery problems such as where a target tissue lacks an intact vascular supply (e.g., a target tissue whose blood flow may be compromised) or is otherwise sequestered from the blood supply (e.g., via the blood-brain barrier of the central nervous system). In some versions of the seeds of the invention that do not contain a radioisotope (e.g., those having only the therapeutically active substance and biodegradable component), after the therapeutically active substance is completely released and the biodegradable component is fully decomposed, no foreign device will remain at the implantation site.
Accordingly, the invention features a brachytherapy seed for implantation into a subject including a biocompatible component, a therapeutically active component that includes a non-radioactive drug, and a radiopaque marker. In this seed, the biocompatible component is physically associated with a therapeutically active component and in contact with the radiopaque marker. The invention also features another brachytherapy seed for implantation into a subject. This seed includes a non-metal biocompatible component, a therapeutically active component comprising a radioisotope, and a radiopaque marker, said biocompatible component being (a) physically associated with a therapeutically active component and (b) in contact with said radiopaque marker, wherein said brachytherapy seed has a size and shape suitable for passing through the bore of a needle having an interior diameter of less than about 2.7 millimeters (10 gauge). Brachytherapy seeds of the invention can have a size and shape suitable for passing through the bore of a needle having an interior diameter of less than about 2.7 millimeters (10 gauge), less than about 1.4 millimeters (15 gauge), less than about 0.84 millimeters (18 gauge), or less than about 0.56 millimeters (24 gauge). In one version of the invention, the seed is shaped into a cylinder having a diameter of between about 0.5 to 3 millimeters and a length 4 to 10 millimeters, e.g., one wherein the diameter is about 0.8 millimeters and the length is about 4.5 millimeters.
In the foregoing seed, the biocompatible component can be biodegradable and include a polymer such as poly(bis(p-carboxyphenoxy) propane anhydride); poly(bis(p-carboxy) methane anhydride); poly(D,L-lactic-coglycolic acid); poly(isobutylcyanoacrylate); a copolymer of polycarboxyphenoxypropane and sebacic acid; open cell polylactic acid; a co-polymer of a poly-fatty cid dimer and sebacic acid; poly(carboxyphenoxy) hexane; poly-1,4-phenylene dipropionic acid; polyisophthalic acid; polydodecanedioic acid; or other polymers described below.
The non-radioactive drug can take the form of stimulating and growth factors; gene vectors; viral vectors; anti-angiogenesis agents; cytostatic, cytotoxic, and cytocidal agents; transforming agents; apoptosis-inducing agents; radiosensitizers; radioprotectants; hormones; enzymes; antibiotics; antiviral agents; mitogens; cytokines; anti-inflammatory agents; immunotoxins; antibodies; or antigens. For example, the non-radioactive can be an anti-neoplastic agent such as paclitaxel, 5-fluorouracil, or cisplatin. It can also be a radiosensitizing agent such as 5-fluorouracil, etanidazole, tirapazamine, BUdR, or IudR.
The radiopaque marker can include platinum, iridium, rhenium, gold, tantalum, bismuth, indium, tungsten, silver, or a radiopaque polymer. Radioisotopes for use in the invention can include 125I and 103Pd.
In another aspect, the invention features a method of making a brachytherapy seed for implantation into a subject. This method includes the steps of: (a) providing a non-metal biocompatible component and a therapeutically active component; (b) physically associating the biocompatible component and the therapeutically active component to form a combination product; and (c) forming the combination product into a seed having a size and shape suitable for passing through the bore of a needle having an interior diameter of less than about 2.7 millimeters (10 gauge), less than about 1.4 millimeters (15 gauge), or less than about 0.84 millimeters (18 gauge), or less than about 0.56 millimeters (24 gauge).
Another method of the invention is a method of making a brachytherapy seed for implantation into a subject. This method includes the steps of: (a) providing a biocompatible component, a therapeutically active component comprising a non-radioactive drug, and a radiopaque marker; (b) physically associating the biocompatible component, the therapeutically active component, and the radiopaque marker to form a combination product; and (c) forming the combination product into a seed having a size and shape suitable for passing through the bore of a needle having an interior diameter of less than about 2.7 millimeters (10 gauge), less than about 1.4 millimeters (15 gauge), or less than about 0.84 millimeters (18 gauge), or less than about 0.56 millimeters (24 gauge).
Yet another method within the invention is a method of making a brachytherapy seed for implantation into a subject. This method includes the steps of: (a) providing a biocompatible component, a therapeutically active component comprising a drug, and a sealed container housing a radioisotope; and (b) physically associating the biocompatible component, the therapeutically active component, and the container into a seed such wherein the biocompatible component and the therapeutically active component at least partially coat the container and the seed has a size and shape suitable for passing through the bore of a needle having an interior diameter of less than about 2.7 millimeters (10 gauge), less than about 1.4 millimeters (15 gauge), or less than about 0.84 millimeters (18 gauge).
In the foregoing methods, the biocompatible component can be biodegradable and include a polymer such as poly(bis(p-carboxyphenoxy) propane anhydride); poly(bis(p-carboxy) methane anhydride); poly(D,L-lactic-coglycolic acid); poly(isobutylcyanoacrylate); a copolymer of poly-carboxyphenoxypropane and sebacic acid; open cell polylactic acid; a co-polymer of a poly-fatty acid dimer and sebacic acid; poly(carboxyphenoxy) hexane; poly-1,4-phenylene dipropionic acid; polyisophthalic acid; polydodecanedioic acid; or other polymers described below. The drug can take the form of stimulating and growth factors; gene vectors; viral vectors; anti-angiogenesis agents; cytostatic, cytotoxic, and cytocidal agents; transforming agents; apoptosis-inducing agents; radiosensitizers; radioprotectants; hormones; enzymes; antibiotics; antiviral agents; mitogens; cytokines; anti-inflammatory agents; immunotoxins; antibodies; or antigens. For example, the drug can be an anti-neoplastic agent such as paclitaxel, 5-fluorouracil, or cisplatin. It can also be a radiosensitizing agent such as 5-fluorouracil, etanidazole, tirapazamine, BUdR, or IUdR.
The radiopaque marker can include platinum, iridium, rhenium, gold, tantalum, bismuth, indium, tungsten, silver, or a radiopaque polymer. Radioisotopes for use in the invention can include 125I and 103Pd. The radioisotope can be contained within a non-radioactive biodegradable component to, e.g., prevent radioactive contamination of a user or an operating room prior to implantation of the seed in a patient.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.